Synthesis of triazole-linked manno- and glucopyranosyl amino acids

Article abstract of DOI:10.1055/s-2007-983813

The synthesis of two types of triazole-linked glycosyl amino acids, at C-4 and at the anomeric position for mannopyranose and glucopyranose derivatives, respectively, via a copper-catalyzed [3+2] cycloaddition of acetylenic amino acid derivatives and azid

Full text of DOI:10.1055/s-2007-983813

PAPER
2647
Synthesis of Triazole-Linked Manno- and Glucopyranosyl Amino Acids
S
ynthesis
a
of
T
riazole
n
-Linked Man
a
no- and Gl
í
n
nosyl
A
mino
a
A
cids V. dos Anjos,a,b Denis Sinou,*a Sebastiao J. de Melo,c Rajendra M. Srivastava*b
a
Laboratoire de Synthèse Asymétrique, UMR 5246-ICBMS, CPE Lyon, Université Claude Bernard Lyon1,
43 boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)78898914; E-mail: sinou@univ-lyon1.fr
b
c
Departamento de Química Fundamental, Universidade Federal de Pernambuco, Cidade Universitária, 50740-540 Recife, PE, Brazil
Fax +55(81)21268442; E-mail: rms@ufpe.br
Departamento de Antibióticos, Universidade Federal de Pernambuco, Cidade Universitária, 50670-901 Recife, PE, Brazil
Received 15 May 2007
the combination of azidoamino acids and acetylenic sug-
ars.6h,12a,c,f,g
Abstract: The synthesis of two types of triazole-linked glycosyl
amino acids, at C-4 and at the anomeric position for mannopyranose
and glucopyranose derivatives, respectively, via a copper-catalyzed
[3+2] cycloaddition of acetylenic amino acid derivatives and azide-
containing glycoside is described.
In a research program involving the synthesis and biolog-
ical evaluation of a series of new aminosugars,13 we pub-
lished a very convenient access to unsaturated 4-
azidocarbohydrates via a palladium-catalyzed substitu-
tion of allylic sugar acetates or carbonates using NaN3 or
Me3SiN3 as the azide source.14 These 4-azidocarbohy-
drates were used in the copper-coupling with various ter-
minal alkynes, allowing an efficient access to some 1,2,3-
triazole-linked glycoconjugates.15 Herein we report the
application of this methodology for the synthesis of some
triazole-linked glycosyl amino acids derived from a-D-
mannopyranose and the extension of this procedure to
glycosyl amino acids derived from a- and b-D-glucopyra-
nose, starting from azidosugars and various protected
amino acids containing a terminal acetylenic function.
Key words: [3+2] cycloaddition, acetylenic amino acid, azidocar-
bohydrate, triazole, glycosyl amino acids
Glycopeptides constitute an important class of natural
compounds which are widely found in living organisms
and play crucial roles in various cellular recognition pro-
cesses.1 The synthesis of such glycopeptides, as well as
the synthesis of models that mimic these natural glyco-
peptides, are attractive goals. The most commonly en-
countered members of this family, or their models, are N-
and O-linked glycopeptides.2 More recently, several ef-
forts have been focused on the synthesis of C-linked gly-
copeptides,2b,3 which are more stable towards chemical
and enzymatic cleavages.
In order to perform the [2+3] cycloaddition, we have to in-
troduce a terminal alkyne moiety in the amino acid. For
this purpose, we prepared three different types of protect-
ed amino acids 1a–c bearing the alkyne group on the acid-
ic function as an amide group, on the amino function as an
amide group, and also on the aromatic ring of the amino
acid (Figure 1).
During the last few years, there has been an increasing in-
terest in the use of the Huisgen’s 1,3-dipolar cycloaddi-
tion reaction of organic azides with terminal acetylenes,4
and particularly after the optimization of the reaction con-
ditions via a copper(I)-catalyzed condensation.5 In carbo-
hydrate chemistry, this copper-catalyzed cycloaddition or
‘click chemistry’ has been used to construct well-defined
glycoconjugates,6 oligosaccharide mimics,7 and macrocy-
clic systems such as glycodendrimers8 or cyclodextrines.9
The synthesis and in situ attachment of saccharides to the
microtiter plate10 as well as the synthesis of multiple la-
belled-carbohydrate oligonucleotides on solid support via
1,2,3-triazole formation have also been described.11
Ph
Ph
NHCO(CH2)2
CONHCH2
MeO2C
BocNH
1a
1b
MeO
O
OCH2
NHBoc
Surprisingly, despite the importance of glycosyl amino
acids, the use of this methodology for the construction of
triazole-linked glycosyl amino acids is scarce. One possi-
bility is the combination of azidosugars with acetylenic
amino acid derivatives,6e–h,12a–e anomeric azides as well as
carbohydrates bearing a spacer between the sugar moiety
and the azido function being used. The other approach is
1c
Figure 1 Acetylenic amino acids
Compounds 1a16 and 1b16a,17 were prepared according to
the literature procedures. The synthesis of acetylenic ami-
no acid 1c was completed in two steps starting from com-
pound 2 obtained from commercially available N-Boc-L-
tyrosine according to the literature18 (Scheme 1). Saponi-
fication of the propargylic ester of compound 2 in a meth-
anolic solution of sodium hydroxide followed by reaction
SYNTHESIS 2007, No. 17, pp 2647–2652
x
x.
x
x
.
2
0
0
7
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983813; Art ID: Z12007SS
© Georg Thieme Verlag Stuttgart · New York

2648
J. V. dos Anjos et al.
PAPER
with diazomethane gave acetylenic amino acid 1c in an These unsaturated triazole-linked glycosyl amino acids
overall yield of 45%.
5a–c were subjected to the dihydroxylation reaction in the
presence of a catalytic amount of OsO4 and N-methylmor-
pholine oxide followed by acetylation of the crude mix-
ture (Scheme 2). As expected, the corresponding triazole-
linked a-D-mannopyranosid-4-yl amino acids 6a–c were
obtained as the sole products in 63, 50, and 61% yield, re-
spectively. Compounds 6a–c were formed by the dihy-
droxylation of the double bond from the less hindered
side, in agreement with the previous findings for similar
compounds.19 The assigned configurations for com-
pounds 6a–c are mainly based on the coupling constant
(J4,5 = 10.7, 10.3, and 10.9 Hz, and J3,4 = 10.7, 11.1, and
10 Hz, respectively), characteristic of an axial–axial dis-
position for H-3, H-4, and H-5.
The starting ethyl 4-azido-2,3,4-trideoxy-a-D-erythro-
hex-2-enopyranoside (4) was prepared according to the
method described previously.14
i
CH2O
O
BocNH
OCH2
2
CH2O
CO2R
BocNH
3 R = H
The reaction of these protected acetylenic amino acids
1a–c was also extended to glucopyranosyl azides 7 and 9.
However, we used the modified protocol recently pub-
lished for similar condensations,20 since it gave higher
chemical yields in shorter reaction times. We performed
the cycloaddition in the presence of CH2Cl2 as the co-sol-
vent, instead of t-BuOH. Under these conditions, the b-
glucopyranosyl azide 7 reacted in an efficient manner
with the acetylenic amino acids 1a–c to give the corre-
sponding triazole-linked b-glycosyl amino acids in good
yields after column chromatography (84, 65, and 73%
yield for 8a, 8b, and 8c, respectively), with retention of
configuration at the anomeric center (Scheme 3). Like-
wise, the a-glucopyranosyl azide 9 reacted with the acet-
ylenic amino acid 1a to give the corresponding triazole-
linked a-glycosyl amino acid 10 in 40% yield. This is a
complementary methodology to that described by
Rutjes’s group,12a who used only the N-protected propar-
gylglycine ester as the acetylenic amino acid, for the syn-
thesis of various triazole-linked glycosyl amino acids.
ii
1c R = Me
Scheme 1 Reagents and conditions: (i) NaOH 2.5%, MeOH, r.t.,
55%; (ii) CH2N2, THF, r.t., 83%.
The reaction of unsaturated carbohydrate 4 with acetylen-
ic amino acid 1a in the presence of a catalytic amount of
Cu(OAc)2 and sodium ascorbate in a 1:1 mixture of tert-
butyl alcohol and water at room temperature under nitro-
gen overnight afforded the 1H-1,2,3-triazole derivative 5a
as the exclusive product in 73% yield after column chro-
matography (Scheme 2). The regioselectivity of the 1,3-
dipolar cycloaddition reaction was assigned according to
the previous results using this methodology and based on
the mechanism proposed by Sharpless et al.5a Under the
same conditions the reaction of carbohydrate 4 with acet-
ylenic amino acids 1b and 1c afforded 1H-1,2,3-triazole
derivatives 5b and 5c in 70 and 60% yield, respectively.
TBDMSO
TBDMSO
AcO
AcO
O
O
i
i
N
O
N
O
+
R
AcO
AcO
AcO
AcO
N3
N
R
N
OEt
N3
OEt
R
OAc
OAc
N
7
N
4
8a–c
1a–c
R
5a–c
AcO
AcO
OTBDMS
ii
O
O
AcO
AcO
AcO
AcO
AcO
O
ii, iii
N
N
N
AcO
AcO
N
AcO
N3
N
9
OEt
10a
N
6a–c
R
Ph
Ph
MeO2C
Ph
MeO2C
Ph
a: R =
c: R =
a: R =
CONHCH2- b: R =
NHCO(CH2)2-
b: R =
NHCO(CH2)2-
CONHCH2-
NHBoc
BocNH
MeO2C
BocNH
MeO2C
OCH2-
OCH2-
c: R =
NHBoc
Scheme 3 Reagents and conditions: (i) 1a–c, CH2Cl2/H2O (1:1),
Cu(OAc)2 (5 mol%), sodium ascorbate (15 mol%), r.t.; (ii) 1a,
CH2Cl2/H2O (1:1), Cu(OAc)2 (5 mol%), sodium ascorbate (15
mol%), r.t.
Scheme
2
Reagents and conditions: (i) t-BuOH–H2O (1:1),
Cu(OAc)2 (20 mol%), sodium ascorbate (40 mol%), r.t.; (ii) OsO4 (2
mol%), NMO, acetone–H2O, r.t.; (iii) Ac2O, C5H5N, r.t.
Synthesis 2007, No. 17, 2647–2652 © Thieme Stuttgart · New York

PAPER
Synthesis of Triazole-Linked Manno- and Glucopyranosyl Amino Acids
2649
(ddd, J = 7.9, 6.0, 5.9 Hz, 1 H, CHN), 4.66 (d, J = 2.5 Hz, 2 H,
CH2C≡C), 4.97 (d, J = 7.9 Hz, 1 H, NH), 6.90 (d, J = 8.6 Hz, 2
In conclusion, we have described a methodology for the
synthesis of ethyl mannopyranoside bearing a triazole
ring at C-4 linked to a protected amino acid moiety via the
acidic or the amino function, or via the aromatic ring. The
same amino acid moieties could be introduced very easily
at the anomeric position of glucopyranose starting from
azidoglucopyranoside.
H
arom), 7.06 (d, J = 8.6 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 28.7, 37.9, 52.6, 54.9, 56.2, 75.9,
79.0, 80.3, 115.3, 129.4, 130.7, 155.5, 157.0, 172.8.
Anal. Calcd for C18H23NO5: C, 64.85; H, 7.21. Found: C, 64.52; H,
7.21.
Unsaturated Triazole Derivatives 5a–c; General Procedure
4-Azidosugar 4 (313 mg, 1 mmol) and the appropriate acetylenic
amino acid derivative 1 (3 mmol) were suspended in 1:1 mixture of
t-BuOH and H2O (4 mL), and THF (2 mL). To this solution was
added a mixture of Cu(OAc)2 (36 mg, 0.2 mmol) and sodium ascor-
bate (79 mg, 0.4 mmol) in t-BuOH–H2O (1 mL). The reaction was
stirred under N2 at r.t. until TLC analysis indicated complete con-
sumption of the product. H2O (3 mL) was added, and the organic
product was extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic layers were dried (Na2SO4). Evaporation of the solvent under
reduced pressure gave a residue that was purified by column chro-
matography on silica gel using the indicated eluent to give the cor-
responding compound 5.
Solvents were dried and distilled by standard methods before use.
All commercially available reagents were used as received. All re-
actions were monitored by TLC analysis (TLC plates GF254 Merck).
Column chromatography was performed on silica gel 60 (230–240
mesh, Merck). Melting points were determined on a Büchi appara-
tus and are uncorrected. Optical rotations were recorded using a
PerkinElmer 241 polarimeter. NMR spectra were recorded with a
1
Bruker AMX 300 spectrometer and referenced as following: H
(300 MHz), internal SiMe4 at d = 0.00, 13C (75 MHz), internal stan-
dard at d = 77.23. Exact mass measurements of the molecular ions
were obtained on a Finnigan Mat 95 XL spectrometer.
N-(tert-Butoxycarbonyl)-N-prop-2-yn-1-yl-L-phenylalaninamide
(1a),16a methyl N-pent-4-ynoyl-L-phenylalaninate (1b),16a,17 prop-2-
N-(tert-Butoxycarbonyl)-N-{[1-(ethyl 6-O-tert-butyldimethyl-
silyl-2,3,4-trideoxy-a-L-erythro-hex-2-enopyranosid-4-yl)-1H-
1,2,3-triazol-4-yl]methyl}-L-phenylalaninamide (5a)
yn-1-yl
N-(tert-butoxycarbonyl)-O-prop-2-yn-1-yl-L-tyrosinate
(2),18 ethyl 4-azido-2,3,4-trideoxy-a-D-erythro-hex-2-enopyrano-
side (4),14 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide (7),21
and 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl azide (9)22 were pre-
pared according to reported procedures. Hexanes used had bp 40–
65 °C.
Prepared from 4 and 1a; colorless solid; yield: 449 mg (73%); mp
20
54 °C; Rf = 0.53 (CH2Cl2–EtOAc, 4:1); [a]D +59.2 (c = 1.0,
CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.00 (s, 3 H, SiCH3), 0.01 (s, 3 H,
SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 1.26 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.39 (s, 9 H, t-C4H9), 3.06 (d, J = 6.8 Hz, 2 H, CH2), 3.53–3.63 (m,
2 H, H-6, CH2CH3), 4.07 (ddd, J = 9.4, 3.0, 2.1 Hz, 1 H, H-5), 4.33
(d, J = 7.2 Hz, 1 H, NH), 4.43 (dd, J = 15.2, 5.6 Hz, 1 H, CH2Ph),
4.50 (dd, J = 15.2, 5.6 Hz, 1 H, CH2Ph), 4.95 (br s, 1 H, NH), 5.13
(br s, 1 H, H-1), 5.32 (br d, J = 9.4 Hz, 1 H, H-4), 5.89 (br d, J = 10.4
Hz, 1 H, H-2), 6.05 (ddd, J = 10.2, 2.8, 2.4 Hz, 1 H, H-3), 6.36 (t,
J = 6.8 Hz, 1 H, CHN), 7.16 (d, J = 7.5 Hz, 2 Harom), 7.24–7.30 (m,
3 Harom), 7.46 (s, 1 H, NCH=).
13C NMR (75 MHz, CDCl3): d = –5.1, –5.0, 15.6, 18.7, 26.2, 28.6,
35.3, 39.0, 55.2, 62.7, 64.5, 71.2, 94.2, 121.5, 127.3, 127.9, 128.9,
129.6, 129.7, 137.0, 145.2, 155.7, 171.8.
HRMS (ESI): m/z [M + Na]+ calcd for C31H49N5O6Si + Na:
638.3349; found: 638.3348.
N-(tert-Butoxycarbonyl)-O-prop-2-yn-1-yl-L-tyrosine (3)
A mixture of propargyl N-(tert-butoxycarbonyl)-O-prop-2-yn-1-yl-
L-tyrosinate (2) (1.12 g, 3.14 mmol) in a methanolic solution of
2.5% NaOH (40 mL) was stirred at r.t. for 3 h. The pH was then ad-
justed to 6.0 by adding a 30% aq solution of HCl, and the mixture
was extracted with EtOAc (3 × 50 mL). Evaporation of the solvent
under reduced pressure followed by purification on silica gel chro-
matography using EtOAc as the eluent afforded acid 3 (550 mg,
20
55%) as a yellow oil; Rf = 0.54 (EtOAc); [a]D +26 (c = 0.5,
CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 9 H, t-C4H9), 2.52 (t,
J = 2.4 Hz, 1 H, C≡CH), 3.03 (dd, J = 14.0, 6.1 Hz, 1 H, CH2Ph),
3.14 (dd, J = 14.0, 5.1 Hz, 1 H, CH2Ph), 4.57 (m, 1 H, CHN), 4.67
(d, J = 2.4 Hz, 2 H, CH2C≡C), 4.95 (d, J = 7.7 Hz, 1 H, NH), 6.92
(d, J = 8.5 Hz, 2 Harom), 7.12 (d, J = 8.5 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 28.7, 37.4, 54.7, 56.2, 76.0, 79.0,
115.4, 130.9, 157.0, 157.1, 176.6.
Anal. Calcd for C31H49N5O6Si: C, 60.46; H, 8.02. Found: C, 59.74;
H, 7.84.
HRMS (ESI): m/z [M + Na]+ calcd for C17H21NO5 + Na: 342.1317;
found: 342.1319.
Methyl N-{3-[1-(Ethyl 6-O-tert-butyldimethylsilyl-2,3,4-
trideoxy-a-D-erythro-hex-2-enopyranosid-4-yl)-1H-1,2,3-tri-
azol-4-yl]propanoyl}-L-phenylalaninate (5b)
Methyl N-(tert-Butoxycarbonyl)-O-prop-2-yn-1-yl-L-tyrosinate
(1c)
Prepared from 4 and 1b; colorless oil; yield: 401 mg (70%); Rf =
0.63 (hexanes–EtOAc, 2:1); [a]D20 +94.7 (c = 1.0, CH2Cl2).
To a solution of 3 (0.2 g, 0.63 mmol) in THF (5 mL) was added
at r.t. an ethereal solution of diazomethane obtained by reacting
N-methyl-N-nitrosotoluene-p-sulfonamide (320 mg, 1.5 mmol)
with ethanolic KOH (34 mg in 0.9 mL). After total consumption of
the starting amino acid, the solvent was removed under reduced
pressure and the residue was purified by silica gel chromatography
using EtOAc as the eluent to afford the methyl ester 1c (174 mg,
83%) as a colorless solid; mp 78–80 °C; Rf = 0.7 (EtOAc); [a]D
+35.7 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 9 H, t-C4H9), 2.52 (t,
J = 2.5 Hz, 1 H, C≡CH), 2.99 (dd, J = 14.0, 6.0 Hz, 1 H, CH2Ph),
3.06 (dd, J = 14.0, 5.9 Hz, 1 H, CH2Ph), 3.71 (s, 3 H, OCH3), 4.54
1H NMR (300 MHz, CDCl3): d = 0.00 (s, 3 H, SiCH3), 0.02 (3 s, 3
H, SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 1.25 (t, J = 7.1 Hz, 3 H,
CH2CH3), 2.61 (t, J = 7.0 Hz, 1 H, CH2), 3.02 (t, J = 7.2 Hz, 2 H,
CH2), 3.07 (m, 1 H, CH2Ph), 3.11 (dd, J = 14.1, 6.0 Hz, 1 H,
CH2Ph), 3.53–3.61 (m, 2 H, CH2CH3, H-6), 3.65 (dd, J = 11.7, 2.1
Hz, 1 H, H-6), 3.71 (s, 3 H, OCH3), 3.87 (dq, J = 9.6, 7.1 Hz, 1 H,
CH2CH3), 4.06 (ddd, J = 9.8, 4.9, 2.1 Hz, 1 H, H-5), 4.85 (ddd,
J = 7.5, 6.0, 5.9 Hz, 1 H, CHN), 5.11(br s, 1 H, H-1), 5.29 (ddd,
J = 9.8, 1.9, 1.7 Hz, 1 H, H-4), 5.90 (br d, J = 10.0 Hz, 1 H, H-2),
6.00 (ddd, J = 10.0, 2.6, 2.6 Hz, 1 H, H-3), 6.16 (br d, J = 7.5 Hz, 1
H, NH), 7.04 (dd, J = 7.6, 1.6 Hz, 2 Harom), 7.20–7.31 (m, 3 Harom),
7.39 (s, 1 H, NCH=).
20
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2650
J. V. dos Anjos et al.
PAPER
13C NMR (75 MHz, CDCl3): d = –5.1, –5.0, 15.6, 18.7, 21.7, 26.2,
38.7, 38.2, 52.6, 53.6, 55.1, 62.7, 64.5, 71.3, 94.2, 120.7, 127.4,
128.2, 128.9, 129.4, 129.5, 136.2, 147.0, 171.9, 172.3.
HRMS (ESI): m/z [M + Na]+ calcd for C35H55N5O10Si + Na:
756.3616; found : 756.3610.
Methyl N-{3-[1-(Ethyl 6-O-tert-butyldimethylsilyl-2,3-di-O-
acetyl-4-deoxy-a-D-mannopyranosid-4-yl)-1H-1,2,3-triazol-4-
yl]propanoyl}-L-phenylalaninate (6b)
Anal. Calcd for C29H44N4O6Si: C, 60.81; H, 7.74. Found: C, 60.68;
H, 7.80.
Prepared from 5b colorless oil; yield: 173 mg (50%); Rf = 0.66
Methyl N-(tert-Butoxycarbonyl)-O-{[1-(ethyl 6-O-tert-butyl-
dimethylsilyl-2,3,4-trideoxy-a-D-erythro-hex-2-enopyranosid-
4-yl)-1H-1,2,3-triazol-4-yl)]methyl}-L-tyrosinate (5c)
(CH2Cl2–EtOAc, 1:1); [a]D20 +52.8 (c = 0.6, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.00 (s, 3 H, SiCH3), 0.05 (s, 3 H,
SiCH3), 0.92 [s, 9 H, SiC(CH3)3], 1.28 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.83 (s, 3 H, CH3), 2.17 (s, 3 H, CH3), 2.62 (t, J = 7.3 Hz, 2 H, CH2),
3.03 (t, J = 7.8 Hz, 2 H, CH2), 3.10 (dd, J = 13.6, 7.8 Hz, 1 H,
CH2Ph), 3.15 (dd, J = 13.6, 5.8 Hz, 1 H, CH2Ph), 3.35 (dd, J = 11.9,
3.4 Hz, 1 H, H-6), 3.63–3.49 (m, 2 H, CH2CH3, H-6), 3.74 (s, 3 H,
OCH3), 3.81 (dq, J = 9.8, 7.1 Hz, 1 H, CH2CH3), 4.33 (br d, J = 10.3
Hz, 1 H, H-5), 4.87 (ddd, J = 7.8, 6.0, 5.8 Hz, 1 H, CHN), 4.91(d,
J = 1.5 Hz, 1 H, H-1), 4.97 (dd, J = 11.1, 10.3 Hz, 1 H, H-4), 5.33
(dd, J = 3.2, 1.7 Hz, 1 H, H-2), 5.85 (dd, J = 11.1, 3.4 Hz, 1 H, H-
3), 6.14 (d, J = 7.5 Hz, 1 H, NH), 7.09 (dd, J = 6.2, 1.7 Hz, 2 Harom),
7.26–7.34 (m, 3 Harom), 7.40 (s, 1 H, NCH=).
Prepared from 4 and 1c; colorless oil; yield: 388 mg (60%); Rf =
0.58 (CH2Cl2–EtOAc, 4:1); [a]D20 +81.9 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.02 (s, 3 H, SiCH3), 0.03 (s, 3 H,
SiCH3), 0.88 [s, 9 H, SiC(CH3)3], 1.27 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.43 (s, 9 H, t-C4H9), 3.01 (dd, J = 14.5, 6.2 Hz, 1 H, CH2Ph), 3.07
(dd, J = 14.1, 6.0 Hz, 1 H, CH2Ph), 3.56–3.72 (m, 3 H, CH2CH3, H-
6), 3.72 (s, 3 H, OCH3), 3.89 (dq, J = 9.5, 7.1 Hz, 1 H, CH2CH3),
4.12 (m, 1 H, H-5), 4.55 (m, 1 H, CHN), 4.98 (br d, J = 7.9 Hz, 1 H,
NH), 5.15 (br s, 1 H, H-1), 5.18 (s, 2 H, OCH2), 5.38 (br d, J = 9.8
Hz, 1 H, H-4), 5.98 (br d, J = 10.0 Hz, 1 H, H-2), 6.05 (ddd,
J = 10.0, 2.5, 2.5 Hz, 1 H, H-3), 6.92 (d, J = 8.6 Hz, 2 Harom), 7.05
(d, J = 8.6 Hz, 2 Harom), 7.70 (s, 1 H, NCH=).
13C NMR (75 MHz, CDCl3): d = –5.1, –4.9, 15.3, 18.7, 20.8, 21.2,
21.6, 26.2, 35.7, 38.2, 52.7, 53.5, 56.4, 62.0, 64.3, 69.2, 69.5, 71.6,
97.7, 122.5, 127.6, 129.0, 129.6, 136.2, 169.5, 170.3, 171.7, 172.3.
13C NMR (75 MHz, CDCl3): d = –5.1, –5.0, 15.6, 18.7, 26.2, 28.7,
52.6, 53.8, 55.3, 62.5, 62.7, 64.6, 71.4, 94.2, 115.1, 122.0, 128.0,
129.0, 129.7, 130.7, 144.9, 155.5, 157.7, 172.7.
HRMS (ESI): m/z [M + Na]+ calcd for C33H50N4O10Si + Na:
713.3194; found: 713.3190.
Anal. Calcd for C32H50N4O8Si: C, 59.42; H, 7.79. Found: C, 58.81;
H, 7.73.
Methyl N-(tert-Butoxycarbonyl)-N-{[1-(ethyl 6-O-tert-butyl-
dimethylsilyl-2,3-di-O-acetyl-4-deoxy-a-D-mannopyranosid-
4-yl)-1H-1,2,3-triazol-4-yl]methyl}-L-tyrosinate (6c)
Dihydroxylation of Unsaturated Triazole Derivatives 6a–c;
General Procedure
Prepared from 5c; colorless solid; yield: 233 mg (61%); mp 63 °C;
To a solution of unsaturated 4-triazolyl glycopeptide 5 (0.5 mmol)
in a 4:1 mixture of acetone–H2O (2 mL), was added OsO4 (0.125
mg, 0.5 mmol, 2 mol%) and N-methylmorpholine-N-oxide (233 mg,
2 mmol) at 0 °C. The mixture was stirred overnight at r.t., then
NaHSO3 (250 mg) was added, and the contents were stirred for 30
min at r.t. The mixture was diluted with H2O (3 mL), and extracted
with EtOAc (2 × 5 mL). The organic phase was separated, dried
(Na2SO4), and the solvent was evaporated to give the corresponding
diol. The crude residue was directly acetylated using Ac2O (153 mg,
1.5 mmol) in pyridine (2 mL) for 1 d. After removing the solvent
under reduced pressure, the residue was purified by column chro-
matography on silica gel using the corresponding eluent to afford
the 4-triazolyl carbohydrate 6.
Rf = 0.81 (CH2Cl2–EtOAc, 4:1); [a]D20 +62.3 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = –0.06 (s, 3 H, SiCH3), 0.00 (s, 3
H, SiCH3), 0.86 [s, 9 H, SiC(CH3)3], 1.23 (t, J = 7.1 Hz, 3 H,
CH2CH3), 1.38 (s, 9 H, t-C4H9), 1.75 (s, 3 H, OCOCH3), 2.10 (s, 3
H, OCOCH3), 2.95 (dd, J = 14.0, 6.2 Hz, 1 H, CH2Ph), 3.01 (dd,
J = 14.0, 5.8 Hz, 1 H, CH2Ph), 3.28 (dd, J = 11.8, 3.2 Hz, 1 H, H-
6), 3.51 (dq, J = 9.8, 7.1 Hz, 1 H, CH2CH3), 3.59 (br d, J = 12.0 Hz,
1 H, H-6), 3.67 (s, 3 H, OCH3), 3.74 (dq, J = 9.8, 7.1 Hz, 1 H,
CH2CH3), 4.32 (br d, J = 10.0 Hz, 1 H, H-5), 4.49 (m, 1 H, CHN),
4.86 (d, J = 1.3 Hz, 1 H, H-1), 4.93 (br d, J = 8.0 Hz, 1 H, NH), 4.97
(dd, J = 10.9, 10.9 Hz, 1 H, H-4), 5.14 (s, 2 H, OCH2), 5.28 (dd,
J = 2.8, 2.1 Hz, 1 H, H-2), 5.85 (dd, J = 11.2, 3.3 Hz, 1 H, H-3), 6.84
(d, J = 8.5 Hz, 2 Harom), 6.99 (d, J = 8.5 Hz, 2 Harom), 7.59 (s, 1 H,
NCH=).
13C NMR (75 MHz, CDCl3): d = –5.2, –4.9, 15.3, 18.6, 20.8, 21.2,
26.2, 28.7, 37.8, 52.6, 54.9, 56.6, 61.9, 62.5, 64.3, 69.2, 69.5, 71.6,
97.8, 115.2, 124.1, 129.0, 130.7, 144.3, 157.7, 169.4, 170.3, 172.7.
HRMS (ESI): m/z [M + H]+ calcd for C36H57N4O12Si: 765.3742;
found: 765.3733.
N-(tert-Butoxycarbonyl)-N-{[1-(ethyl 6-O-tert-butyldimethyl-
silyl-2,3-di-O-acetyl-4-deoxy-a-D- mannopyranosid-4-yl)-1H-
1,2,3-triazol-4-yl]methyl}-L-phenylalaninamide (6a)
Prepared from 5a; colorless solid; yield: 231 mg (63%); mp 66 °C;
Rf = 0.75 (CH2Cl2–EtOAc, 1:1); [a]D20 +39.4 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.00 (s, 3 H, SiCH3), 0.05 (s, 3 H,
SiCH3), 0.92 [s, 9 H, SiC(CH3)3], 1.29 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.39 (s, 9 H, t-C4H9), 1.83 (s, 3 H, CH3), 2.16 (s, 3 H, CH3), 3.05 (d,
J = 6.8 Hz, 2 H, CH2), 3.34 (dd, J = 11.9, 3.0 Hz, 1 H, H-6), 3.56
(dq, J = 9.8, 7.2 Hz, 1 H, CH2CH3), 3.63 (br d, J = 11.9 Hz, 1 H, H-
6), 3.80 (dq, J = 9.8, 7.2 Hz, 1 H, CH2CH3), 4.38–4.35 (m, 2 H, H-
5, NH), 4.41 (dd, J = 15.2, 5.6 Hz, 1 H, CH2Ph), 4.52 (dd, J = 15.2,
5.8 Hz, 1 H, CH2Ph), 4.91 (br s, 1 H, H-1), 4.94 (br s, 1 H, NH), 4.98
(dd, J = 10.7, 10.7 Hz, 1 H, H-4), 5.33 (dd, J = 2.8, 1.7 Hz, 1 H, H-
2), 5.83 (dd, J = 10.7, 3.2 Hz, 1 H, H-3), 6.48 (dd, J = 5.8, 5.6 Hz,
1 H, CHN), 7.14 (d, J = 7.4 Hz, 2 Harom), 7.22–7.32 (m, 3 Harom),
7.48 (s, 1 H, NCH=).
Glucopyranosyl-Linked Triazole Derivatives 8a–c and 10a;
General Procedure
Azidosugar 7 or 9 (1 mmol) and the appropriate acetylenic amino
acid (1.1 mmol) were suspended in 1:1 mixture of CH2Cl2 and H2O
(4 mL). To this solution was added a mixture of Cu(OAc)2 (36 mg,
0.2 mmol) and sodium ascorbate (79 mg, 0.4 mmol). The resulting
mixture was stirred under N2 at r.t. until TLC analysis indicated
complete consumption of the azidosugar. The mixture was diluted
with CH2Cl2 (5 mL) and H2O (5 mL). The organic layer was sepa-
rated, and the aqueous phase was extracted again with CH2Cl2 (5
mL). The combined organic layers were dried (Na2SO4). Evapora-
tion of the solvent under reduced pressure gave a residue that was
purified by column chromatography on silica using the indicated
eluent to give the corresponding 1,2,3-triazoles 8a–c or 10a.
13C NMR (75 MHz, CDCl3): d = –6.5, –6.3, 13.9, 17.2, 19.4, 19.8,
24.8, 27.2, 33.9, 55.1, 60.5, 62.9, 67.9, 68.0, 70.0, 96.4, 122.3,
126.0, 127.7, 128.3, 135.5, 168.0, 168.9, 170.3.
Synthesis 2007, No. 17, 2647–2652 © Thieme Stuttgart · New York

PAPER
Synthesis of Triazole-Linked Manno- and Glucopyranosyl Amino Acids
2651
N-(tert-Butoxycarbonyl)-N-({1-[2,3,4,6-tetra-O-acetyl-b-D-glu-
copyranosyl]-1H-1,2,3-triazol-4-yl}methyl)-L-phenylalanin-
amide (8a)
N-(tert-Butoxycarbonyl)-N-({1-[2,3,4,6-tetra-O-acetyl-a-D-glu-
copyranosyl]-1H-1,2,3-triazol-4-yl}methyl)-L-phenylalanin-
amide (10a)
Prepared from 7 and 1a; colorless solid; yield: 439 mg (65%); mp
Prepared from 9 and 1a; colorless solid; yield: 270 mg (40%); mp
135 °C; Rf = 0.71 (EtOAc); [a]D20 –19.7 (c = 1.0, CH2Cl2).
82 °C; Rf = 0.65 (EtOAc); [a]D20 +62.0 (c = 0.5, CH2Cl2).
1H NMR (300 MHz, DMSO-d6): d = 1.31 (s, 9 H, t-C4H9), 1.79 (s,
3 H, OCOCH3), 1.97 (s, 3 H, OCOCH3), 1.99 (s, 3 H, OCOCH3),
2.03 (s, 3 H, OCOCH3), 2.74 (dd, J = 13.6, 10.0 Hz, 1 H, CH2Ph),
2.94 (dd, J = 13.6, 4.3 Hz, 1 H, CH2Ph), 4.05–4.18 (m, 3 H, H-6,
CHN), 4.33 (d, J = 5.5 Hz, 2 H, CH2N), 4.37–4.40 (m, 1 H, H-5),
5.17 (dd, J = 9.4, 9.2 Hz, 1 H, H-4), 5.55 (dd, J = 9.4, 9.2 Hz, 1 H,
H-3), 5.61 (dd, J = 9.4, 8.5 Hz, 1 H, H-2), 6.33 (d, J = 8.7 Hz, 1 H,
H-1), 6.95 (d, J = 8.5 Hz, 1 Harom), 7.18–7.24 (m, 5 H, 4 Harom, NH),
8.06 (s, 1 H, NCH=), 8.50 (br t, J = 5.0 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 20.5, 20.9, 20.9, 21.0, 28.6, 35.2,
40.0, 61.9, 68.0, 70.7, 73.1, 75.4, 86.0, 127.2, 129.0, 129.7, 137.0,
169.2, 169.7, 170.3, 170.9, 171.8.
HRMS (ESI): m/z [M + H]+ calcd for C31H42N5O12: 676.2830;
found: 676.2857.
1H NMR (300 MHz, DMSO-d6): d = 1.40 (s, 9 H, t-C4H9), 1.88 (s,
3 H, OCOCH3), 2.03 (s, 3 H, OCOCH3), 2.06 (s, 3 H, OCOCH3),
2.07 (s, 3 H, OCOCH3), 3.06 (d, J = 7.0 Hz, 2 H, CH2Ph), 4.01 (dd,
J = 12.4, 1.9 Hz, 1 H, H-6), 4.26 (dd, J = 12.4, 3.9 Hz, 1 H, H-6),
4.30–4.35 (m, 2 H, H-5, CHN), 4.47 (dd, J = 15.8, 5.6 Hz, 1 H,
CH2N), 4.52 (dd, J = 15.8, 5.8 Hz, 1 H, CH2N), 4.95 (br s, 1 H, NH-
Boc), 5.26 (dd, J = 9.8, 9.4 Hz, 1 H, H-4), 5.32 (dd, J = 10.0, 6.0 Hz,
1 H, H-2), 6.25 (d, J = 6.0 Hz, 1 H, H-1), 6.26 (dd, J = 10.0, 9.4 Hz,
1 H, H-3), 6.43 (dd, J = 5.8, 5.6 Hz, 1 H, NH), 7.15 (dd, J = 7.7, 2.1
Hz, 2 Harom), 7.25–7.32 (m, 3 Harom), 7.44 (s, 1 H, NCH=).
13C NMR (75 MHz, CDCl3): d = 18.5, 18.7, 18.8, 26.4, 28.6, 32.9,
54.9, 66.2, 67.9, 68.5, 69.3, 79.6, 122.7, 125.2, 126.9, 127.5, 134.6,
167.8, 168.2, 168.7, 1169.5, 169.6.
HRMS (ESI): m/z [M + Na]+ calcd for C31H41N5O12 + Na: 698.2649;
found: 698.2649.
Methyl N-(3-{1-[2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl]-
1H-1,2,3-triazol-4-yl}propanoyl)-L-phenylalaninate (8b)
Prepared from 7 and 1b; colorless solid; yield: 531 mg (84%); mp
155 °C; Rf = 0.38 (EtOAc); [a]D20 +10.0 (c = 1.0, CH2Cl2).
Acknowledgment
We are indebted to the CAPES/COFECUB program no. 334/01 for
financial support, and CNPq-Brazil for providing a fellowship
(J.A.).
1H NMR (300 MHz, DMSO-d6): d = 1.78 (s, 3 H, OCOCH3), 1.96
(s, 3 H, OCOCH3), 1.99 (s, 3 H, OCOCH3), 2.03 (s, 3 H, OCOCH3),
2.41 (t, J = 7.4 Hz, 2 H, CH2), 2.74 (t, J = 7.3 Hz, 2 H, CH2), 2.87
(dd, J = 13.6, 9.2 Hz, 1 H, CH2Ph), 3.02 (dd, J = 13.6, 5.6 Hz, 1 H,
CH2Ph), 3.60 (s, 3 H, OCH3), 4.04 (dd, J = 12.4, 2.3 Hz, 1 H, H-6),
4.14 (dd, J = 12.4, 5.3 Hz, 1 H, H-6), 4.37 (ddd, J = 9.8, 5.3, 2.3 Hz,
1 H, H-5), 4.47 (ddd, J = 11.1, 5.6, 3.4 Hz, 1 H, CHN), 5.15 (dd,
J = 9.6, 9.6 Hz, 1 H, H-4), 5.55 (dd, J = 9.2, 9.0 Hz, 1 H, H-3), 5.59
(dd, J = 9.0, 8.9 Hz, 1 H, H-2), 6.29 (d, J = 8.9 Hz, 1 H, H-1), 7.19–
7.31 (m, 5 Harom), 8.06 (s, 1 H, NCH=), 8.43 (d, J = 7.7 Hz, 1 H,
NH).
References
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13C NMR (75 MHz, CDCl3): d = 20.5, 20.9, 20.9, 21.0, 21.6, 35.5,
38.1, 52.7, 53.5, 61.9, 68.1, 70.6, 73.1, 75.3, 85.9, 120.3, 127.5,
128.9, 129.6, 136.3, 147.6, 169.2, 169.8, 170.3, 170.9, 171.6, 172.4.
Anal. Calcd for C29H36N4O12: C, 55.06; H, 5.74. Found: C, 54.77;
H, 5.82.
Methyl N-(tert-Butoxycarbonyl)-O-{[1-(2,3,4,6-tetra-O-acetyl-
b-D-glucopyranosyl)-1H-1,2,3-triazol-4-yl]methyl}-L-tyrosi-
nate (8c)
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Prepared from 7 and 1c; colorless solid; yield: 515 mg (73%); mp
158 °C; Rf = 0.83 (EtOAc); [a]D20 –1.3 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 9 H, t-C4H9), 1.77 (s, 3 H,
OCOCH3), 1.97 (s, 3 H, OCOCH3), 2.00 (s, 3 H, OCOCH3), 2.03 (s,
3 H, OCOCH3), 2.78 (dd, J = 13.4, 10.0 Hz, 1 H, CH2Ph), 2.91 (dd,
J = 13.4, 4.9 Hz, 1 H, CH2Ph), 3.60 (s, 3 H, OCH3), 4.04–4.16 (m,
3 H, H-6, CHN), 4.37 (ddd, J = 10.0, 5.1, 2.6, 1 H, H-5), 5.11 (s, 2
H, OCH2), 5.18 (dd, J = 9.8, 9.6 Hz, 1 H, H-4), 5.56 (dd, J = 9.4, 9.4
Hz, 1 H, H-3), 5.68 (dd, J = 9.4, 9.1 Hz, 1 H, H-2), 6.38 (d, J = 9.0
Hz, 1 H, H-1), 6.94 (d, J = 8.5 Hz, 2 Harom), 7.16 (d, J = 8.5 Hz, 2
Harom), 7.27 (d, J = 8.1 Hz, 1 H, NH), 8.54 (s, 1 H, NCH=).
13C NMR (75 MHz, CDCl3): d = 20.5, 20.8, 20.9, 21.1, 28.7, 37.9,
52.6, 61.9, 62.3, 68.0, 70.6, 73.0, 75.5, 86.1, 115.3, 121.5, 126.2,
129.2, 130.8, 145.4, 157.6, 169.3, 169.7, 170.3, 170.9, 172.7.
HRMS (ESI): m/z [M + H]+ calcd for C32H43N4O14: 707.2776;
found: 707.2763.
Synthesis 2007, No. 17, 2647–2652 © Thieme Stuttgart · New York

2652
J. V. dos Anjos et al.
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Synthesis 2007, No. 17, 2647–2652 © Thieme Stuttgart · New York